Genetic Variant CPA2:p.Pro219Gln (chr7-130276698-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001869.3(CPA2):c.656C>A(p.Pro219Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P219L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CPA2
NM_001869.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.38

Publications

0 publications found

Variant links:

Genes affected

CPA2 (HGNC:2297): (carboxypeptidase A2) Three different forms of human pancreatic procarboxypeptidase A have been isolated. The encoded protein represents the A2 form, which is a monomeric protein with different biochemical properties from the A1 and A3 forms. The A2 form of pancreatic procarboxypeptidase acts on aromatic C-terminal residues and is a secreted protein. [provided by RefSeq, Dec 2008]

CPA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001869.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPA2	NM_001869.3	MANE Select	c.656C>A	p.Pro219Gln	missense	Exon 7 of 11	NP_001860.2	P48052

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPA2	ENST00000222481.9	TSL:1 MANE Select	c.656C>A	p.Pro219Gln	missense	Exon 7 of 11	ENSP00000222481.4	P48052
CPA2	ENST00000416698.1	TSL:5	n.*207C>A		non_coding_transcript_exon	Exon 8 of 8	ENSP00000395582.1	J3QT58
CPA2	ENST00000487259.5	TSL:2	n.671C>A		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460092

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726494

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110436

Other (OTH)

AF:

0.00

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-0.54

MutationAssessor

Pathogenic

4.1

PhyloP100

2.4

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.33

Sift

Benign

0.036

Sift4G

Uncertain

0.040

Polyphen

1.0

Vest4

0.67

MutPred

0.93

Gain of sheet (P = 0.0827)

MVP

0.57

MPC

0.52

ClinPred

0.99

GERP RS

2.8

Varity_R

0.76

gMVP

0.88

Mutation Taster

=43/57

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over